scholarly journals Toll-Like Receptor Mediated Activation of Natural Autoantibody Producing B Cell Subpopulations in an Autoimmune Disease Model

2019 ◽  
Vol 20 (24) ◽  
pp. 6152 ◽  
Author(s):  
Szabina Erdő-Bonyár ◽  
Judit Rapp ◽  
Tünde Minier ◽  
Gábor Ráth ◽  
József Najbauer ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Subset ◽  
Mrna Levels ◽  
Toll Like Receptor ◽  
Autoantibody Production ◽  
Altered Expression ◽  
Cell Subpopulations ◽  
And Function ◽  
Natural Autoantibody

Altered expression and function of the Toll-like receptor (TLR) homologue CD180 molecule in B cells have been associated with autoimmune disorders. In this study, we report decreased expression of CD180 at protein and mRNA levels in peripheral blood B cells of diffuse cutaneous systemic sclerosis (dcSSc) patients. To analyze the effect of CD180 stimulation, together with CpG (TLR9 ligand) treatment, on the phenotype defined by CD19/CD27/IgD/CD24/CD38 staining, and function (CD69 and CD180 expression, cytokine and antibody secretion) of B cell subpopulations, we used tonsillar B cells. After stimulation, we found reduced expression of CD180 protein and mRNA in total B cells, and CD180 protein in B cell subpopulations. The frequency of CD180+ cells was the highest in the CD19+CD27+IgD+ non-switched (NS) B cell subset, and they showed the strongest activation after anti-CD180 stimulation. Furthermore, B cell activation via CD180 induced IL-6 and natural autoantibody secretion. Treatment with the combination of anti-CD180 antibody and CpG resulted in increased IL-6 and IL-10 secretion and natural autoantibody production of B cells. Our results support the role of CD180 in the induction of natural autoantibody production, possibly by NS B cells, and suggest an imbalance between the pathologic and natural autoantibody production in SSc patients.

Porphyromonas Gingivalis Lipopolysaccharide-induced B Cell Differentiation by Toll-like Receptors 2 and 4

2021 ◽  
Vol 28 ◽  
Author(s):  
Sumei Liu ◽  
Guojing Liu ◽  
Qingxian Luan ◽  
Yongping Ma ◽  
Xiaoqian Yu
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Subset ◽  
Mrna Levels ◽  
B Cell Differentiation ◽  
Toll Like Receptor ◽  
Regulatory B Cells ◽  
E Coli ◽  
Porphyromonas Gingivalis Lipopolysaccharide

Background: : Porphyromonasgingivalis (P. gingivalis) is a pathogenic bacterium widely present in subgingival plaques of patients with periodontitis. It induces periodontitis with bone loss as its main feature by changing the number and composition of symbiotic microorganisms, as well as inducing the natural immune response of the host. However, the mechanism of the latter remains unclear. Objective:: This study aims to investigate the effect of P. gingivalis lipopolysaccharide (LPS) on regulatory B cells (Breg) in the occurrence and development of periodontitis. Method:: We detected the mRNA levels of IL-10 in B cells under the stimulation of P. gingivalis LPS and/or E. coli LPS, distinguished IL-10-producing cells from different B cell subgroups using flow cytometry. Through toll-like receptor (TLR) knockout mice, the role of TLR2 and TLR4 in this process were also evaluated. Results : Results showed that P. gingivalis stimulated B cells to produce IL-10 via TLR2/4. CD5+B1 subset is the main source of IL-10+Breg cell. Under P. gingivalis LPS stimulation, CD5+IgM+CD93-IL-10+B cell subset increased significantly which was regulated through TLR2/4. Conclusion: The results of this study provides new insights into the immunopathogenic mechanism of P. gingivalis, preliminarily discussed the effect of P. gingivalis on the production of Breg, and present a theoretical foundation for subsequent investigations on the occurrence and development of periodontitis.

scholarly journals NFκB1 is essential to prevent the development of multiorgan autoimmunity by limiting IL-6 production in follicular B cells

2016 ◽  
Vol 213 (4) ◽  
pp. 621-641 ◽  
Author(s):  
Elisha de Valle ◽  
George Grigoriadis ◽  
Lorraine A. O’Reilly ◽  
Simon N. Willis ◽  
Mhairi J. Maxwell ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Receptor Activation ◽  
Spontaneous Generation ◽  
B Cell Differentiation ◽  
Toll Like Receptor ◽  
Intrinsic Loss ◽  
And Function ◽  
Follicular B Cells

We examined the role of NFκB1 in the homeostasis and function of peripheral follicular (Fo) B cells. Aging mice lacking NFκB1 (Nfκb1−/−) develop lymphoproliferative and multiorgan autoimmune disease attributed in large part to the deregulated activity of Nfκb1−/− Fo B cells that produce excessive levels of the proinflammatory cytokine interleukin 6 (IL-6). Despite enhanced germinal center (GC) B cell differentiation, the formation of GC structures was severely disrupted in the Nfκb1−/− mice. Bone marrow chimeric mice revealed that the Fo B cell–intrinsic loss of NFκB1 led to the spontaneous generation of GC B cells. This was primarily the result of an increase in IL-6 levels, which promotes the differentiation of Fo helper CD4+ T cells and acts in an autocrine manner to reduce antigen receptor and toll-like receptor activation thresholds in a population of proliferating IgM+ Nfκb1−/− Fo B cells. We demonstrate that p50-NFκB1 represses Il-6 transcription in Fo B cells, with the loss of NFκB1 also resulting in the uncontrolled RELA-driven transcription of Il-6. Collectively, our findings identify a previously unrecognized role for NFκB1 in preventing multiorgan autoimmunity through its negative regulation of Il-6 gene expression in Fo B cells.

scholarly journals B Cell Subsets as Severity-Associated Signatures in COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Víctor A. Sosa-Hernández ◽  
Jiram Torres-Ruíz ◽  
Rodrigo Cervantes-Díaz ◽  
Sandra Romero-Ramírez ◽  
José C. Páez-Franco ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Subset ◽  
Hierarchical Cluster ◽  
Specific Subset ◽  
Respiratory Parameters ◽  
Cell Subpopulations ◽  
Severity Of The Disease ◽  
B Cell Subsets ◽  
Relationship Of

BackgroundSARS-CoV-2 infection represents a global health problem that has affected millions of people. The fine host immune response and its association with the disease course have not yet been fully elucidated. Consequently, we analyze circulating B cell subsets and their possible relationship with COVID-19 features and severity.MethodsUsing a multiparametric flow cytometric approach, we determined B cell subsets frequencies from 52 COVID-19 patients, grouped them by hierarchical cluster analysis, and correlated their values with clinical data.ResultsThe frequency of CD19+ B cells is increased in severe COVID-19 compared to mild cases. Specific subset frequencies such as transitional B cell subsets increase in mild/moderate cases but decrease with the severity of the disease. Memory B compartment decreased in severe and critical cases, and antibody-secreting cells are increased according to the severity of the disease. Other non-typical subsets such as double-negative B cells also showed significant changes according to disease severity. Globally, these differences allow us to identify severity-associated patient clusters with specific altered subsets. Finally, respiratory parameters, biomarkers of inflammation, and clinical scores exhibited correlations with some of these subpopulations.ConclusionsThe severity of COVID-19 is accompanied by changes in the B cell subpopulations, either immature or terminally differentiated. Furthermore, the existing relationship of B cell subset frequencies with clinical and laboratory parameters suggest that these lymphocytes could serve as potential biomarkers and even active participants in the adaptive antiviral response mounted against SARS-CoV-2.

scholarly journals B-Cell Compartmental Features and Molecular Basis for Therapy in Autoimmune Disease

2021 ◽  
Vol 8 (6) ◽  
pp. e1070
Author(s):  
Chao Zhang ◽  
Tian-Xiang Zhang ◽  
Ye Liu ◽  
Dongmei Jia ◽  
Pei Zeng ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Type I Interferon ◽  
Type I ◽  
Autoantibody Production ◽  
Interferon Pathway ◽  
Proinflammatory Activity ◽  
Cell Subpopulations ◽  
Molecular Landscape

Background and ObjectivesTo assess the molecular landscape of B-cell subpopulations across different compartments in patients with neuromyelitis optica spectrum disorder (NMOSD).MethodsWe performed B-cell transcriptomic profiles via single-cell RNA sequencing across CSF, blood, and bone marrow in patients with NMOSD.ResultsAcross the tissue types tested, 4 major subpopulations of B cells with distinct signatures were identified: naive B cells, memory B cells, age-associated B cells, and antibody-secreting cells (ASCs). NMOSD B cells show proinflammatory activity and increased expression of chemokine receptor genes (CXCR3 and CXCR4). Circulating B cells display an increase of antigen presentation markers (CD40 and CD83), as well as activation signatures (FOS, CD69, and JUN). In contrast, the bone marrow B-cell population contains a large ASC fraction with increased oxidative and metabolic activity reflected by COX genes and ATP synthase genes. Typically, NMOSD B cells become hyperresponsive to type I interferon, which facilitates B-cell maturation and anti–aquaporin-4 autoantibody production. The pool of ASCs in blood and CSF were significantly elevated in NMOSD. Both CD19− and CD19+ ASCs could be ablated by tocilizumab, but not rituximab treatment in NMOSD.DiscussionB cells are compartmentally fine tuned toward autoreactivity in NMOSD and become hyperreactive to type I interferon. Inhibition of type I interferon pathway may provide a new therapeutic avenue for NMOSD.

The CD21low B Cell Population Is Composed of an Anergic and an Immunostimulatory Germinal Center-like B Cell Subset

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1425-1425
Author(s):  
Alexander Shimabukuro-Vornhagen ◽  
María García Márquez ◽  
Rieke Fischer ◽  
Kerstin Wennhold ◽  
Juliane Iltgen ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Functional State ◽  
Cell Subset ◽  
Cell Compartment ◽  
Inflammatory Conditions ◽  
Cell Subpopulations ◽  
B Cell Subsets ◽  
Antigen Presenting ◽  
Human B Cell

Abstract In recent years we have gained an increased understanding of the complexity of B cell biology and function. It has become increasingly recognized that apart from antibody production B cells exert many more function. B cells serve as antigen-presenting cells (APC), they contribute to immunoregulation and represent an important source of cytokines and chemokines. A deeper understanding of the role of B cells in the pathophysiology of human diseases has been hampered by the lack of well-defined functional B cell subsets. We therefore aimed to identify novel human B cell subsets which could serve as biomarkers or targets of therapeutic intervention. Using a transcriptomic approach combined with flowcytometric immune assessment of healthy human subjects and patients we were able to identify several functional B cell subpopulations with relevance to human disease. We were able to define a CD21low CD86pos human B cell subset with strong antigen-presenting capacity which gradually develops from conventional resting B cells under the continuous stimulation via CD40. These cells were phenotypically and functionally distinct from CD21low CD86neg B lymphocytes, which represent anergic B cells. Using calcium flux assays and phospho-specific flow cytometry we were able to show that the CD21low B cell subsets displayed distinct signaling states. Both CD21low B cell subpopulations had an impaired response to B cell receptor stimulation. However, CD21low CD86pos B cells had higher basal calcium levels and basal phosphorylation of BCR-associated signaling molecules such as Syk and Erk. Contrary to CD21low CD86neg B cells, which demonstrated poor antigen-presenting capacity, CD21low CD86pos B cells were potent immunostimulatory antigen-presenting cells. CD21low CD86pos B cells were increased in acute inflammation and autoimmune diseases such as rheumatoid arthritis. CD21low CD86neg B cells, on the other hand, were increased in chronic inflammatory conditions such as chronic HIV infection. The balance between the CD21low B cell subsets varied with the functional state of the B cell compartment in inflammatory conditions and could be used to classify the functional state of the B cell compartment. In summary, we have identified several novel human B cell subsets with distinct functions. Given the large number of B cell-directed drugs which are in clinical development or already approved it seems likely that an increased knowledge of the human B cell subsets will not only provide important insights into the pathology of immune-mediated diseases but will also result in novel therapeutic strategies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phenotype and Function of CD25-Expressing B Lymphocytes Isolated from Human Umbilical Cord Blood

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Sylvie Amu ◽  
Mikael Brisslert
Keyword(s):  
B Cells ◽  
Cord Blood ◽  
B Cell ◽  
Cell Subset ◽  
Cell Populations ◽  
Human Umbilical Cord Blood ◽  
Human Umbilical Cord ◽  
Common Denominator ◽  
Human Cord Blood ◽  
And Function

Background. We have shown that approximately 30% of human peripheral blood B-cells express CD25. B cells expressing CD25 display a mature phenotype belonging to the memory B-cell population and have a better proliferative and antigen-presenting capacity. The aim of the present study was to characterize the CD25-expressing subset of B cells in human cord blood.Material and Methods. Mononuclear cell fraction from human cord blood (n=34) and peripheral adult blood (n=22) was sorted into CD20+CD25+and CD20+CD25-B-cell populations. Phenotype and function of these B-cell populations were compared using flow cytometry, proliferation, cytokine production, and immunoglobulin secretion.Results. CD25-expressing B cells are a limited population of cord blood mononuclear cells representing 5% of the CD20+B cells. They are characterised by high expression of CD5 in cord blood and CD27 in adult blood. CD25-expressing B cells express a functional IL-2 receptor and high levels of CC-chemokine receptors and spontaneously produce antibodies of IgG and IgM subclass.Conclusions. CD25 expression is a common denominator of a specific immunomodulatory B-cell subset ready to proliferate upon IL-2 stimulation, possibly ready to migrate and home into the peripheral tissue for further differentiation/action.

scholarly journals Carrier-directed anti-hapten responses by b-cell subsets

1977 ◽  
Vol 146 (1) ◽  
pp. 1-10 ◽  
Author(s):  
GK Lewis ◽  
JW Goodman
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Burst Size ◽  
Cell Subset ◽  
B Cell Activation ◽  
Cell Subpopulations ◽  
Activation Pathways ◽  
B Cell Subsets

The capacity of the trinitrophenyl (TNP) haptenic group, coupled to a series of chemically dissimilar carriers, to cross-stimulate putative T- dependent and T-independent murine B-cell subpepulations was determined by using an in vitro limiting dilution technique to generate primary IgM responses. It was found that TNP-Ficoll and TNP-dextran, two T- independent antigens with little or no polyclonal mitogenicity, stimulate the same population of anti-TNP precursors, which is distinct from the precursor population activated by TNP-bacterial lipopolysaccharide (LPS), a T-independent polyclonal mitogen, or TNP-horse erythrocytes (HRBC), a T-dependent antigen. On the other hand, TNP-LPS and TNP-HRBC activate the same precursor population, indicating that LPS can substitute for the T- cell signal in T-dependent B-cell responses, whereas nonmitogenic T- independent antigens cannot. However, the cumulative evidence from this and other laboratories strongly indicates that LPS and T-dependent antigens activate B cells by different mechanisms. Of particular interest, LPS is incapable of activating B cells responsive to weakly- or nonmitogenic T-independent antigens. Based on clonal burst size, T-dependent antigens are capable of inducing greater antigen-specific B-cell proliferation than T-independent antigens. However, TNP conjugates of Ficoll and dextran, which are relatively poor inducers of polyclonal B-cell activation, induced larger anti-TNP clones than did TNP-LPS, a strong polyclonal mitogen. The findings reinforce the evidence favoring existence of multiple B- cell subpopulations with distinctive activation pathways. They also strengthen the proposition that a given B-cell subset can be activated by more than one mechanism.

scholarly journals Anti-Pneumococcal Capsular Polysaccharide Antibody Response and CD5 B Lymphocyte Subsets

2015 ◽  
Vol 83 (7) ◽  
pp. 2889-2896 ◽  
Author(s):  
Leen Moens ◽  
Bert Verbinnen ◽  
Kris Covens ◽  
Greet Wuyts ◽  
Marina Johnson ◽  
...  
Keyword(s):  
B Cells ◽  
Antibody Response ◽  
B Cell ◽  
B Lymphocyte ◽  
Capsular Polysaccharide ◽  
Cell Subset ◽  
Healthy Human ◽  
Cell Subpopulations ◽  
Polysaccharide Antibody

The role of CD19+CD5+and CD19+CD5−B cell subpopulations in the antibody response to pneumococcal capsular polysaccharides (caps-PSs) is controversial. In the present study, we evaluated the role of human CD19+CD5+and CD19+CD5−cell populations in the serotype-specific antibody response to caps-PS. After vaccination of 5 healthy human adults with Pneumovax (23-valent pneumococcal polysaccharide vaccine [PPV23]), IgG anti-caps-PS serotype 4 antibody-producing cells resided mainly in the CD19+CD5−B cell subset, as assessed by enzyme-linked immunosorbent spot (ELISpot) analysis. Moreover, in a humanized SCID mouse model, CD19+CD5−B cells were more effective than CD19+CD5+cells in producing IgG anti-cap-PS antibodies. Finally, an association was found between the level of IgG anti-caps-PS antibodies and the number of CD19+CD5−B cells in 33 humans vaccinated with PPV23. Taken together, our data suggest that CD5 defines a functionally distinct population of B cells in humans in the anti-caps-PS immune response.

scholarly journals Toll-Like Receptor Homolog CD180 Expression Is Diminished on Natural Autoantibody-Producing B Cells of Patients with Autoimmune CNS Disorders

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Zsófia Hayden ◽  
Szabina Erdő-Bonyár ◽  
Beáta Bóné ◽  
Noémi Balázs ◽  
Kornélia Bodó ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Bacterial Infections ◽  
Citrate Synthase ◽  
Memory B Cells ◽  
Igg Antibody ◽  
Autoantibody Production ◽  
B Cell Subsets ◽  
Natural Autoantibody

Purpose. Decreased expression of TLR homolog CD180 in peripheral blood B cells and its potential role in antibody production have been described in autoimmune diseases. Effectiveness of anti-CD20 therapy in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) strengthens the role of B cells in the pathogenesis. Therefore, we aimed to investigate the CD180 expression of peripheral blood B cell subsets in NMOSD and MS patients and analyze the levels of natural anti-citrate synthase (CS) IgG autoantibodies and IgG antibodies induced by bacterial infections reported to play a role in the pathogenesis of NMOSD or MS. Methods. We analyzed the distribution and CD180 expression of peripheral blood B cell subsets, defined by CD19/CD27/IgD staining, and measured anti-CS IgM/G natural autoantibody and antibacterial IgG serum levels in NMOSD, RRMS, and healthy controls (HC). Results. We found decreased naïve and increased memory B cells in NMOSD compared to MS. Among the investigated four B cell subsets, CD180 expression was exclusively decreased in CD19+CD27+IgD+ nonswitched (NS) memory B cells in both NMOSD and MS compared to HC. Furthermore, the anti-CS IgM natural autoantibody serum level was lower in both NMOSD and MS. In addition, we found a tendency of higher anti-CS IgG natural autoantibody levels only in anti-Chlamydia IgG antibody-positive NMOSD and MS patients. Conclusions. Our results suggest that reduced CD180 expression of NS B cells could contribute to the deficient natural IgM autoantibody production in NMOSD and MS, whereas natural IgG autoantibody levels show an association with antibacterial antibodies.

Telomere Elongation in B-Cells Is Independent of Class Switching.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1542-1542
Author(s):  
Alexander Roeth ◽  
Dirk de Beer ◽  
Marc Seifert ◽  
Astrid Mueller ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Telomere Length ◽  
Germinal Center ◽  
Cell Subset ◽  
Memory B Cells ◽  
Double Positive ◽  
Telomere Elongation ◽  
Cell Subpopulations ◽  
B Cell Subsets

Abstract BACKGROUND: In contrast to human granulocytes and T-cells with a quite homogenous decrease in telomere lengths over age, telomere lengths of peripheral blood B-cell populations are highly heterogeneous with average telomere lengths of B-cells remaining relatively constant from middle age onward (Baerlocher et al, J. Leuk. Biol. 2003). So far, telomere elongation has been described in highly proliferating germinal center B-cells during the development from naive B-cells to memory B-cells (Norrback et al, Eur J Haematol 2001). During this same time period the process of class-switch recombination (CSR) occurs. Our aims were to analyze the telomere lengths in different B-cell subsets in order to elucidate telomere length dynamics in relationship to CSR. PATIENTS and METHODS: Buffy coats from 14 healthy donors were enriched for CD19+ B cells by magnetic cell separation. Naive B cells (IgM+/IgD+/CD27−), IgM-only B cells (IgM+/IgD−/low/CD27+), double-positive B cells (IgM+/IgD+/CD27+) and class-switched memory B cells (IgM−/IgD−/CD27+) were further separated by cell sorting. Telomere length of sorted B-cell subpopulations was measured by automated multicolour flow-FISH. RESULTS: Naive B-cells presented the shortest telomere length values (average telomere length, n=14: 7.2 kb ± 0.7 kb) compared to the other B-cell subsets. In comparison to the naive B-cell subset, the IgM only B-cell subset had 13% longer telomeres (average telomere length, n=14: 8.1 kb ± 1.3 kb), the double-positive B-cell subset had 10% longer telomeres (average telomere length, n=14: 7.9 kb ± 0.8 kb) and the memory B-cell subset had 22% longer telomeres (average telomere length, n=14: 8.7 kb ± 1.1 kb) (p < 0.0001). CONCLUSIONS: We are able to confirm longer telomeres in memory B cells than in naive B cells. For the first time, however, we can demonstrate that longer telomeres are also found in non-class switched B-cells. Based on these results telomere elongation does not coincide with the process of CSR. Additional studies are needed to assess whether telomere elongation can only take place in the germinal center or whether certain B-cell subsets are able to elongate their telomeres independent from the germinal center.

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